Paclitaxel is a diterpene taxane found in very low concentration in the bark of Pacific yew tree Taxus brevifolia. Therefore, a number of semi-synthetic strategies have been developed for its synthesis from more readily available 10-DAB. However, the taxane nucleus is highly prone to degradation and semisynthetic crude materials are often produced contamined with structurally similar impurities, thereby necessitating elaborate purification procedure using HPLC. In view of the above facts, it becomes highly desirable to develop alternative routes for synthesis of paclitaxel which involves minimal degradation along the synthetic pathway. Any synthetic protocol for the semi-synthesis of paclitaxel/docetaxel generally consists of:
a. selective acylation/protection at similarly reactive C-7 and C-10 hydroxyl groups. Among the 1, 7, 10 and 13-hydroxyl groups in 10-DAB, the order of reactivity is 7>10>13>1. Therefore, selective esterification of 13-hydroxyl group requires prior protection of both 7 and 10-hydroxyl groups. Furthermore, if acetyl group is required in the final product, as in the case of paclitaxel, then 7-hydroxyl is to be protected first followed by acetylation of 10-hydroxyl. This requires selection of appropriate protecting groups, which can be put selectively and removed selectively under mild condition. Recently, we have explored the use of haloalkyl acid chlorides as protecting groups (U.S. Provisional Patent Application 60/311077). These haloalkonoyl groups undergo hydrolysis faster than unsubstituted alkonoyl groups and their deprotection causes minimum degradation. We have found that such haloalkyl acid chlorides specifically 2-halo/2,2-dihaloalkyl acid chlorides can be used for selective protection in taxanes and can be selectively deprotected.
b. selective esterification of 13-hydroxyl group with a suitably protected N-benzoylphenylisoserine. It has been found that α-hydroxy-β-amidoaryl moiety at the 13-hydroxyl of the taxane moiety is essential for its anti-cancer activity (Wani et al J Am Chem Soc 93, pp 2325, 1971). Esterification at 13-hydroxyl of taxane is very sluggish due to its stereo-electronic disposition. It is known that the esterification step proceeds to completion with cyclic forms of α-hydroxy-β-amidoarylcarboxylic acids. Furthermore, when cyclic forms of C-13 side chains are used, no 2′-epimers are obtained as side product. Therefore, new cyclic forms of side chains, which undergo facile coupling with suitably protected 10-DAB in high yield under simple reactions condition without their use in large excess, are required for developing better and more efficient alternative routes for synthesis of paclitaxel and its analogs.
c. conversion of side chain precursor parts into side chain and removal of the protecting groups from baccatin part. These reactions conditions should be mild in nature to afford final material in high yield with very few side products. For successful commercial production, it is desirable that the crude semi-synthetic taxane is produced with such purity that it could easily be purified into pharmaceutical grade material.
Most of the nitrogen protecting groups used so far in oxazolidine carboxylic acid require either harsh acidic condition or hydrogenolysis for their removal. Thus, eg. U.S. Pat. No. 5,476,954 to Bourzat et al describes an oxazolidine side chain having a tert-butoxy carbonyl protecting group on the nitrogen atom. After coupling with suitably protected 10-DAB, this protecting group is removed by treating the coupled product in an acidic medium to obtain an amine which is then converted into the corresponding benzoyl derivative. Also, Mas et al in the U.S. Pat. No. 5,616,739 describes a process in which the coupled product, obtained from coupling an oxazolidine carboxylic acid and a protected 10-DAB, is treated in an acidic medium to achieve simultaneous removal of side chain protecting groups and 10-hydroxyl protecting group. The resultant amine is then suitably protected to obtain the taxane.
On the other hand, U.S. Pat. No. 5,637,723 issued to Rhone Poulenc Roer S A in 1997 described an oxazolidine carboxylic acid, which incorporated benzoyl group as the nitrogen-protecting group. Consequently, the coupled product obtained from the oxazolidine carboxylic acid and protected 10-DAB, upon deprotection did not require to be protected by a benzoyl group. Again this procedure requires deprotection of the coupled product in an acidic medium.